Schistosomiasis, caused by a blood fluke, is a chronic, morbid and 'neglected' disease affecting as many as 700 million people globally. Ensuing anemia, abdominal pain, impaired physical and cognitive development degrade individual and societal productivity. Infection also elevates the risk of acquiring HIV, making treatment of schistosomiasis a priority for HIV-prevention. Treatment and control of schistosomiasis relies on just one drug, praziquantel (PZQ). Apart from concerns over possible drug resistance, PZQ has a number of failings. First, the standard oral dose of 40 mg/kg is rarely completely effective, with reported cure rates anywhere between 50 and 90%. Second, PZQ primarily kills adult parasites allowing immature worms to escape that upon maturation go on to generate morbidity. Third, PZQ is rapidly metabolized to a series of metabolites of which only one is partially as active as the parent molecule. In addition, the drug has a repellent taste and is marketed as a large 600 mg tablet making compliance, especially for children, difficult. The World Health Organization encourages the discovery and development of new drug candidates. The UCSF Center for Discovery and Innovation in Parasitic Diseases (www.cdipd.org) has identified commercial anti-hypercholesterolemia statin drugs - inhibitors of HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-CoA reductase or HMGR) - as potent schistosomicidal compounds. Statins first came to our attention during phenotypic whole-organism screens designed specifically to identify potential therapeutics for the schistosome parasite, screens that have now been adapted to quantitative, high-content imaging platforms. In advance of a detailed structure-activity lead optimization program to develop specific anti-schistosomal statins, we propose two Specific Aims. First, in partnership with an industry leader in statin drug development (Merck Sharp & Dohme Corp. (Merck)), we will employ quantitative and 'targeted' phenotypic screening of privileged statin libraries to obtain a preliminary understanding of the structural determinants of statin analogs that kill the parasite in vitro, including those that improve killing activity over commercial statins already tested. Secondly, we will optimize and standardize the recombinant expression of active Schistosoma mansoni HMGR, which will be central to deriving the kinetic and crystallographic data necessary to prosecute a subsequent lead optimization program to identify candidate molecules for treatment of schistosomiasis. The engagement of a large pharmaceutical company like Merck represents a watershed moment for schistosomiasis R&D since the discovery of PZQ 40 years ago. The combination of Merck's expertise in statin chemistry and UCSF's parasitological/screening expertise will short-list novel and more potent anti-schistosomal molecules. The proposed research activity is in advance of a collaborative and longer-term lead optimization program that will continue to utilize the tools employed or developed herein.